Conditions Treated With Regenerative Medicine

Regenerative medicine focuses on unleashing our body’s ability to heal itself by utilizing biologic therapy. By using a combination of growth factors and cellular therapies, we are now able to treat a vast array of conditions. Multiple studies have shown improvement with the following:

  • Osteoarthritis
  • Rotator Cuff Tears
  • Meniscal Tears
  • Cartilage Defects
  • Tendonitis & Tendinopathy
  • Muscle Injuries
  • Ligament Tears
  • Lateral Epicondylitis of the Elbow (Tennis Elbow)
  • Achilles Tendonitis
  • Hamstring Tear & Tendonitis
  • Patellar Tendonitis
  • Plantar Fasciitis
  • Osteochondritis Dissecans (OCD)
  • Avascular Necrosis (AVN)
  • Non-Union of Fractures

Bone marrow aspirate concentrate contains mesenchymal stem cells which provide the cells necessary for tissue repair. In addition, the nucleated cells in bone marrow aspirate concentrate can signal the body to deliver growth factors and cytokines that initiate and organize tissue repair.

Platelet Rich Plasma

Platelet rich plasma, or PRP as it is commonly called, is a type of growth factor (GF) therapy. Blood is drawn from the patient’s vein and placed in a sterile tube where it is spun in a centrifuge. The blood is separated into its components, and platelets are concentrated from the blood creating platelet-rich plasma. PRP can do several things, including attracting mesenchymal stem cells, macrophages, and fibroblasts. Mesenchymal stem cells can turn into cells that form cartilage, tendon, and bone, while macrophages are important modulators of the inflammatory response. Fibroblasts form collagen and extra-cellular matrix proteins and are activated by cytokines produced from the macrophages. Together this results in cell proliferation and can stimulate and improve healing.

Stem Cells

The human body is formed of tissue that originates from 3 types of cells in the germ layer: endoderm, ectoderm, and mesoderm. The mesoderm gives rise to the muscles, tendons, ligaments, and remaining connective tissue in our body. The cells of the germ layer give rise to stem cells, and the stem cells formed from the mesoderm are called mesenchymal stem cells (MSCs). Stem cells are useful because of the qualities they hold. Stem cells have the ability to reproduce and form more stem cells. Stem cells also have the ability to differentiate, or mature and turn into different types of cells. In addition, stem cells have the ability to mobilize, activate, and control other types of cells around them through various signaling pathways by producing several growth factors and cytokines.

Mesenchymal Stem Cells

Mesenchymal stem cells are derived from the mesoderm, the cell lineage that forms muscle, tendon, ligament, bone, cartilage, and other connective tissue. Mesenchymal stem cells have the ability to differentiate into cells that form cartilage, bone, muscle, tendon, ligament, and nerve. Mesnchymal stem cells can be found in several places including bone marrow, fat, synovial tissue, and periostem. Mesenchymal stem cells, however, are most abundant and easiest to access from bone marrow aspirate and fat. Bone marrow aspirate has been the most commonly reported source of mesenchymal stem cells to stimulate healing.

MSCs are a rich source of several growth factors and cytokines, which have a paracrine and immunomodulatory effect.

MSCs have an immunosuppressive effect by adjusting the activation of natural killer cells, dendritic cells, macrophages, and T and B lymphocytes. MSCs have advantageous anti-inflammatory and antifibrotic actions to maximize their therapeutic effects in the lesion site. Studies published to date have reported favorable outcomes, with most focusing on clinical improvement versus quality of regeneration.

Bone Marrow Aspirate Concentrate

Bone marrow aspirate concentrate (BMAC) has been approved by the United States Food and Drug Administration (FDA) as a rich source of stem cells and growth factors. The mesenchymal stem cells obtained from bone marrow have both an anti-inflammatory as well as regenerative effect of damaged tissue. Bone marrow aspirate concentrate influences the healing response in several ways. It decreases cell death (apoptosis) as well as decreases inflammation. It also activates cell growth and division (proliferation), turns cells into different types of cells (differentiation), and increases blood vessel formation (angiogenesis) by way of signaling pathways. As a result, bone marrow aspirate concentrate aids in tissue repair by providing a direct cell source in the form of mesenchymal stem cells, as well as cytokines and growth factors which promote tissue healing.

BMAC contains several growth factors such as PDGF, TGF-β, and VEGF which are secreted by MSCs. These have high chondrogenic potential and can serve as a chemoattractant.

When obtaining stem cells, the harvest site plays a major role in the number of cells obtained. Iliac crest has the highest concentration of bone marrow-derived mesenchymal stem cells. When the bone marrow aspirate is centrifuged, it concentrates the cells 6-7 times. Bone marrow-derived mesenchymal stem cells have been shown to have a greater cartilage forming effect than fat-derived stem cells. The number of mesenchymal stem cells are counted by colony forming units (CFU). The older we get, the less colony forming units we have.

Direct comparison of chondrogenic potential of adipose and bone marrow-derived cells has shown greater efficiency and quality of chondrogenesis with bone marrow-derived cells. MSCs in BMAC have the potential to self-renew, undertake clonal expansion, and differentiate into different musculoskeletal tissues. MSCs also have an immunoregulatory role and may enhance the normal healing response.

Bioactive Factors

Bioactive factors include platelet-derived growth factor (PDGF), transforming growth factor beta (TGF-β), vascular endothelial growth factor (VEGF), fibroblast growth factor (FGF), insulin-like growth factor I (IGF-I), granulocyte-macrophage colony-stimulating factor (GMCSF), bone morphogenetic protein (BMP-2 and 7), and interleukins (IL-1β, 6, 8). Bioactive factors are assigned to have anabolic and anti-inflammatory effects resulting in positive effects on cartilage repair and treatment of osteoarthritis. PDGF can play a specific role in cartilage regeneration and maintaining homeostasis via MSC proliferation and inhibition of IL-1β-induced chondrocyte apoptosis/inflammation pathway. TGF-β has a role in stimulating chondrogenesis, inhibiting inflammation, and enhancing cartilage healing or regeneration.

Rotator Cuff Tear

The rotator cuff refers to four muscles that form a common tendon that surrounds the humeral head. When functioning normally, the rotator cuff gives the shoulder strength and stability. When the rotator cuff tendon tears, however, the shoulder does not function well. Rotator cuff tears are a common problem in sports medicine, and there has been much effort in the literature to find ways to prevent and treat rotator cuff tears.

PRP injections have become an attractive option for circumventing the potential risks of corticosteroid injections

Standard conservative treatment for rotator cuff tears has focused on medications such as non-steroidal anti-inflammatories (NSAIDs), exercises and physical therapy to improve strengthening and motion, and injections into the shoulder. Corticosteroid injections have been used extensively in the treatment of rotator cuff tears to help reduce the inflammation around the rotator cuff tear. These injections can often provide good short term pain relief, but do not provide any long-term healing potential or address the tendon tear. Several recent studies have shown deleterious effects on tendon quality with repeated cortisone injections in the shoulder. Some clinical studies have reported higher revision rates after rotator cuff surgery with multiple pre-operative cortisone injection. These findings have pushed us to look for additional options to treat these tears to encourage healing and prevent the potential negative effects of corticosteroids on tendon quality and tendon healing if surgery is pursued.

PRP injections have been found to increase the local concentrations of platelets and growth factors, including PDGR, VEGF, TGF-β, and epidermal growth factor, which have been implicated as important factors in the early healing process. PRP injections have shown promising results in the treatment of lateral epicondylitis, knee osteoarthritis, and shoulder disorders.

Bone marrow aspirate concentrate injections are another option to help enhance healing of rotator cuff tears and rotator cuff repairs. Bone marrow aspirate concentrate utilizes mesenchymal stem cells combined with growth factors and cytokines to deliver a powerful biologic injection that induces and enhances healing. Bone marrow aspirate concentrate contains stem cells and higher levels of growth factors than PRP alone.

BMAC released significantly higher levels of growth factors IGF, TGF-β1, and VEGF than PRP. The nucleated cells in BMAC are three times higher than that in PRP.

When conservative measures fail, arthroscopic surgery is performed to repair the rotator cuff tear. The tendon-to-bone insertion site is restored with this procedure. Several studies, however, have shown that this insertion site is the weakest link in the repair construct and can be prone to failure if complete healing at the tendon and bone interface is not restored. Regenerative medicine offers options to enhance the healing rate of the tendon-to-bone insertion site by utilizing biologic therapy such as platelet-rich plasma and bone marrow aspirate concentrate with bone marrow derived mesenchymal stem cells.

The local application of bone marrow aspirate concentrate (BMAC) after rotator cuff repair enhanced the mechanical strength of the tendon-to-bone junction. Improved biological healing was also observed histologically in BMAC-treated groups.

Platelet-rich plasma injections into the shoulder have become one option to help reduce the negative effects of repeated corticosteroid injections while at the same time providing healing potential for the rotator cuff tendon. By increasing the local concentration of platelets and multiple growth factors, PRP injections can enhance the healing process when a rotator cuff tear is present. A recent study compared patients with partial rotator cuff tears who received corticosteroid injections versus platelet-rich plasma injections. Those patients who received PRP injections into the shoulder had superior improvement in pain and function compared with those that received a corticosteroid injection.

Bone marrow aspirate concentrate (BMAC) combined with platelet-rich plasma (PRP) improved pain and shoulder function in patients with partial tears of the rotator cuff tendon. In addition, tear size decreased after BMAC-PRP injection.

Several studies have shown the benefits of bone marrow aspirate concentrate with regards to rotator cuff repair. One study showed BMAC-treated rotator cuff repairs showed better collagen fiber organization and continuity then isolated repairs or those treated with PRP alone. The BMAC-treated rotator cuff repairs had higher values with biomechanical properties and a higher ultimate load-to-failure than isolated repairs alone. These results highlight the function of bone marrow aspirate concentrate to improve rotator cuff tendon repair quality. Another study found that rotator cuff partial tears treated with bone marrow aspirate concentrate had improved shoulder function, reduced pain, and decrease in tear size.

Meniscal Tear

Injury to the meniscus is a common problem that can lead to development of osteoarthritis in the future. Meniscal tears, however, can be challenging to get to heal. Studies have shown that bone marrow aspirate concentrate injections into the knee may provide a successful treatment options to enhance the healing of meniscal tears.

Early in vitro work has shown BMAC has potential to promote macroscopic and microscopic healing of meniscal defects.

Cartilage Defects

Injury to the cartilage in the joint is a common problem that can lead to arthritis. Cartilage defects, however, can be challenging to get to heal. The cartilage in the joint does not have a blood supply or nerve innervation, and relies entirely on diffusion to obtain the necessary nutrients and oxygen. This makes healing of focal cartilage defects difficult.

Previous attempts to restore cartilage have focused on surgical techniques such as abrasion arthroplasty or microfracture. These marrow stimulation techniques rely on the formation of fibrocartilage repair tissue being generated. Compared to our normal joint cartilage (hyaline cartilage), this fibrocartilage repair tissue has poor compressive stiffness under load, as well as inferior wear characteristics. This has led us to look for other options to form hyaline cartilage, a much more durable repair tissue. Regenerative medicine offers several promising options.

To enhance the healing potential or articular cartilage, regenerative medicine has utilized biologic therapy including injections with platelet-rich plasma and bone marrow derived mesenchymal stem cells. There are several studies that demonstrate the positive effects that platelet-rich plasma has on cartilage damage and degeneration. These studies have shown improvements in clinical symptoms as well as joint function.

Clinical data suggests BMAC may help stimulate a more robust hyaline cartilage repair tissue response.

Bone marrow aspirate concentrate has also shown promising clinical results with regards to repairing cartilage injury. Bone marrow derived mesenchymal stem cells have the ability to turn into cells important for cartilage formation. Bone marrow aspirate concentrate has elevated concentrations of several growth factors that stimulate cartilage repair and prevent cartilage degeneration. The combination of elevated levels of growth factors, cytokines, and mesenchymal stem cells play a key role in the tissue recovery and wound healing capabilities of bone marrow aspirate concentrate. Some of these studies use isolated injections, where others combine the injections with a surgical marrow stimulation technique like microfracture or abrasion arthroplasty. These studies conclude that bone marrow aspirate concentrate and an increased concentration of mesenchymal stem cells help to stimulate a more robust response in regards to hyaline cartilage repair tissue formation.

PRP versus BMAC

When selecting a biologic therapy in regenerative medicine, it is important to understand the major differences between platelet-rich plasma (PRP) and bone marrow aspirate concentrate (BMAC). PRP is prepared by drawing autologous venous blood and centrifuging it twice to prepare the final product. No sedation is needed for the procedure. BMAC is harvested from the iliac crest of the pelvis while the patient is under light sedation. The bone marrow aspirate is then centrifuged twice to obtain the final product.

There are several key differences between the contents of PRP and BMAC. PRP has an elevated platelet concentration along with increased levels of multiple growth factors. These growth factors play a role in recruiting healing cells, cartilage and tissue repair, activation of mesenchymal stem cells, and control the inflammatory response.

Platelet-rich plasma has increased platelet concentration and provides multiple growth factors with known roles in target cell activation, cell recruitment, cartilage matrix production, and modulation of the inflammatory response.

BMAC also has an elevated platelet concentration. In addition, BMAC contains multiple growth factors, but to a much higher extent than what is seen in PRP. One of the most important components of BMAC is the bone marrow derived mesenchymal stem cells. These stem cells have the ability to reproduce, differentiate into different cell types, mobilize to create blood flow and healing, and influence and control the environment they are present in. The components of bone marrow aspirate concentrate work together to deliver stem cells to damaged tissue and enhance the healing environment.

  • Bone Marrow Aspirate Concentrate (BMAC) contains a high concentration of bone marrow-derived platelets in addition to Mesenchymal Stem Cells (MSCs). These platelets contain a significant number of growth factors, chemokines, and cytokines identified in BMAC. They differ in their properties from the platelets found in peripheral blood used for Platelet-Rich Plasma (PRP) preparation. Cartilage 2018;9(2):161-170. Cotter EJ et. al, Cartilage 2018
  • Bone Marrow Aspirate Concentrate contains growth factors from the transforming growth factor-β(TGF-β) superfamily, which have been linked to chondrocyte proliferation and Mesenchymal Stem Cell differentiation. Cartilage 2018;9(2):161-170. Cotter EJ et. al, Cartilage 2018
  • Another key growth factor present in Bone Marrow Aspirate Concentrate is platelet-derived growth factor (PDGF), that promotes wound healing, collagen synthesis, the suppression of interleukin-1β (a pro-inflammatory cytokine), and the enhancement of bone morphogenetic proteins-2 (BMP-2) and 7 (BMP-7) that contribute to the production of the extracellular matrix and chondrocyte proliferation. Cartilage 2018;9(2):161-170. Cotter EJ et. al, Cartilage 2018
  • BMAC is a rich source of growth factors PDGF and TGF-β affording it great potential to induce chondrogenesis in Mesenchymal Stem Cells. Cartilage 2018;9(2):161-170. Cotter EJ et. al, Cartilage 2018

Summary of the defining characteristics of PRP versus BMAC:

BMAC PRP
IL-1ra ++++ +
IL-1ra/IL-1β ++ –
MSC +++ –
TGF-β1 +++ +++
IL-1β ++ –
VEGF ++++ +
PDGF +++ +++
IL-8 ++++ –

(Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018)

  • Interleukin 1 receptor antagonist (IL-1ra) is a naturally occurring antagonist that competitively binds to IL-1β and IL-1α cell surface receptors, thereby inhibiting IL-1 catabolism. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018
  • Interleukin 1 beta (IL-1β) is a pro-inflammatory cytokine secreted by monocytes, neutrophils, and Mesenchymal stem cells. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018
  • Mesenchymal Stem Cells (MSCs) – There are four hallmarks characteristics that define stem cells: the ability to reproduce, differentiate into multiple cell types, mobilize for purposes of angiogenesis, and exert paracrine signaling functions that influence the environment in which they are present. Multipotent stem cells inherently have a narrow scope of cells into which they may differentiate when compared to embryonic or induced pluripotent stem cells. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018
  • Transforming growth factor beta-1 (TGF-β1) has been shown to stimulate chondrogenesis of MSC’s, inhibit IL-1β-mediated inflammation, and enhance cartilage healing. Its concentration parallels platelet concentration. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018
  • Vascular endothelial growth factor (VEGF) stimulates wound healing and collagen deposition. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018
  • Platelet-derived growth factor (PDGF) induces Mesenchymal Stem Cell proliferation and inhibits IL-1β-induced chondrocyte apoptosis and inflammation. PDGF concentrations correspond to platelet concentrations. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018
  • Interleukin 8 is a pro-inflammatory cytokine secreted by monocytes, neutrophils, and MSCs. IL-8 is a potent chemoattractant for neutrophils, which secrete IL-1, and in turn can stimulate monocytes to produce IL-8. Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018

Comparison of Cellular Composition of PRP versus BMAC:

PRP BMAC
WBC x 11.8x
Neutrophils x 19x
Monocytes x 11x
Lymphocytes x 7x
Platelets x X
Mesenchymal Stem Cells – X

(Cassano JM et. al, Knee Surg Sports Traumatol Arthrosc 2018)

References

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